In recent years there has been an increasing awareness of the serious public health problem posed by the complications which often accompany long-term diabetes, including neuropathy, nephropathy and retinopathy. Up to the present time no clear knowledge exists of the mechanism responsible for the development of these sequelae nor is any therapeutic agent available which could be used in conjunction with insulin for their prevention. The diverse nature of the disorders seen, such as the demyelination of peripheral nerve, cell death and new blood vessel proliferation in the retina, thickening of basement membrane in the kidney glomerulus, increased aggregation of erythrocytes and platelets, decreased deformability of erythrocytes, decreased phagocytosis and adherence by leukocytes and decreased viability of fibroblasts, suggest that other biochemical changes occur in this disease beyond the well-known derangements in glucose and amino acid metabolism. Some of the phenomena mentioned, including the behavior of the formed elements of the blood, are suggestive of alterations at the cell surface membrane, particularly in its glycoprotein or glycolipid components. Indeed recent publications dealing with liver and red cell plasma membranes of streptozotocin-diabetic rats indicate that changes in the cell surface carbohydrates do occur. These findings have great implications since they suggest that a disorder in the metabolism of complex carbohydrates may exist in diabetes. The proposed study will attempt to define the structural basis of such cell surface alterations and to explore the generality of the membrane changes in various tissues of the diabetic. In addition, complex saccharide metabolism will be studied in an integrated manner by measurement of sugar nucleotide pools, the activity of the enzymes involved in forming and degrading these intermediates and the level of the glycosyltransferases responsible for glycoprotein and glycolipid synthesis. These latter investigations have value beyond the field of diabetes to many areas of medicine and biology since they bear on the regulation of the synthesis of the complex carbohydrates, which is as yet poorly understood.